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. 2006 Apr;74(4):2187-95.
doi: 10.1128/IAI.74.4.2187-2195.2006.

Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide

Richard Malley  1 , Amit Srivastava, Marc Lipsitch, Claudette M Thompson, Claire Watkins, Arthur Tzianabos, Porter W Anderson
Affiliations

Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide

"V体育平台登录" Richard Malley et al. Infect Immun. 2006 Apr.

Abstract (V体育ios版)

Serotype-specific immunity to Streptococcus pneumoniae is conferred by antibodies to the capsular polysaccharides, which define the 90 known serotypes VSports手机版. Whether antibody to the species-common cell wall polysaccharide (C-Ps) is protective has been a matter of controversy. Here we show that C-Ps given intranasally with mucosal adjuvant increased the resistance of mice to experimental nasopharyngeal colonization by capsulated S. pneumoniae of serotype 6B. This immunity could be induced in mice congenitally lacking immunoglobulin but was dependent upon CD4+ T cells. Elimination of the charged amino group on the polymer backbone by N acetylation of C-Ps reduced the immunity, as did treatment of the mice with antibody to the cytokine interleukin-17A at the time of challenge, both consistent with the hypothesis of T-cell activation due to the zwitterionic motif of the polymer. C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy against S. pneumoniae. .

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Figures

FIG. 1.
FIG. 1.
Effect of intranasal immunization with C-Ps upon pneumococcal colonization in C57BL/6 mice. For panels A and C, each data point represents the density of nasopharyngeal colonization in CFU/ml of tracheal wash for each mouse, with sterile samples assigned a value of 5 (half the lower limit of detection of 10). The horizontal bar shows the geometric mean CFU/ml for each group. A. Immunization was with C-Ps in doses indicated and with 1 μg of cholera toxin where indicated. Three weeks after secondary immunization, the mice (n = 16 for each group) were challenged intranasally with a strain of serotype 6B. Reduction of CFU recovered from tracheal wash was significant for mice immunized with 200 μg C-Ps plus CT versus CT alone (P = 0.004 by the Kruskal-Wallis test with Dunn's correction). B. Serum antibody determination in mice (n = 6 for each group) that received CT or CPS (200 μg) plus CT. IgG serum antibodies to C-Ps were measured by ELISA; mice that received CPS (200 μg) plus CT had significantly more anti-C-Ps IgG 4 weeks after the second intranasal immunization (P = 0.002 by the Mann-Whitney U test). C. Immunization was with 200 μg of C-Ps plus 4 μg of cholera toxin B subunit or CTB alone. Mice (n = 12 for each group) were challenged with a strain of serotype 6B (comparison of density of colonization between mice that received C-Ps plus CTB versus CTB alone, P = 0.049 by Student's t test of log-transformed data).
FIG. 2.
FIG. 2.
Effect of further treatment of C-Ps with trichloroacetic acid or periodate. A. Silver-stained SDS-PAG of 100-μg samples of C-Ps (Statens Seruminstitut) before (lane 1) and after (lane 2) extraction with TCA for 1 day at 4°C as described in Materials and Methods. B and C. Effect of immunization with TCA-treated C-Ps plus CT (B) or periodate-oxidized C-Ps plus CT (C) upon nasopharyngeal colonization of C57BL/6 mice by serotype 6B. Mice were immunized intranasally with 1 μg of CT and 200 μg of C-Ps with and without prior treatment as indicated. The horizontal bar shows the geometric mean CFU/ml for each group. Protection by immunization with TCA-treated C-Ps plus CT was significant versus that achieved by CT alone (P = 0.0007 by the Mann-Whitney U test) and similar to that with C-Ps plus CT (P = 0.74). Oxidation of C-Ps with periodate reduced protection (P = 0.21 versus immunization with CT alone by the Mann-Whitney U test), whereas the control preparation of C-Ps incubated with glycerol-pretreated periodate was significantly effective (P = 0.01 versus CT alone by the Mann-Whitney U test) (n = 8 to 10 mice per group).
FIG. 3.
FIG. 3.
Effect of intranasal immunization with C-Ps upon pneumococcal serotype 6B nasopharyngeal colonization in immunodeficient mice. Mice were immunized with 1 μg of CT and 200 μg of C-Ps or CT alone as indicated. The P values are calculated by the Mann-Whitney U test for protection versus CT alone. A. muMT−/− mice, deficient in immunoglobulin were significantly protected compared with CT controls (P = 0.01; 16 mice per group). B. Nude mice (nu−/−) were not protected (P > 0.05) in contrast to their heterozygote controls (nu+/−) (P = 0.01; 10 mice per group). C. Mice with a disruption of the MHC class II H2-Ab1 gene were not protected (P > 0.1; 12 mice per group). The horizontal bar shows the geometric mean CFU/ml for each group.
FIG. 4.
FIG. 4.
Effect of N acetylation of C-Ps upon immunity to NP colonization. C-Ps was acetylated to convert the free amino to N acetyl groups (52). C57B/6 mice were immunized with 1 μg of CT and 200 μg of C-Ps or N-acetylated C-Ps as indicated. The density of colonization in the tracheal wash of individual mice is shown. The horizontal bar shows the geometric mean CFU/ml for each group. N-acetylated C-Ps plus CT was not effective in reducing colonization (P > 0.05 versus CT alone by the Kruskal-Wallis test with Dunn's correction), whereas untreated C-Ps plus CT was effective (P < 0.01) (n = 6 to 10 mice per group).
FIG. 5.
FIG. 5.
Secretion of IL-17A following immunization with C-Ps and role in immunity to NP colonization. A) Cultured splenocytes from mice immunized with C-Ps plus CT or CT alone were stimulated with the agents indicated for 72 h, after which IL-17A production was measured by ELISA. Increased IL-17A production due to C-Ps or killed pneumococci was noted in splenocytes from mice immunized with C-Ps plus CT. Shown is a representative experiment of at least three experiments, which gave similar results. dmem, Dulbecco modified Eagle medium; conA, concanavalin A. B) Mice immunized with C-Ps plus CT 4 weeks earlier received intraperitoneal injections of rabbit serum with or without anti-mouse rabbit IL-17A antibody at the time of pneumococcal i.n. challenge and 3 days later. Mice were sacrificed on day 6, and nasal washes were collected for quantification of pneumococcal colonization. The horizontal bar shows the geometric mean CFU/ml for each group. Immunized mice that received IL-17A antibody had no reduction in the density of NP colonization (nonsignificant versus CT alone), whereas immunized mice that received only rabbit serum had significantly fewer recovered pneumococci from tracheal washes (P = 0.01 versus mice that received CT alone) (n = 8 to 10 mice per group).
FIG. 6.
FIG. 6.
Effect of intranasal immunization with C-Ps upon invasive disease in C57BL/6 mice. Mice immunized with C-Ps plus CT or CT alone were challenged by intranasal aspiration of type 3 strain WU2, and survival was assessed twice daily. Mice immunized with C-Ps plus CT survived significantly longer than mice that received CT alone (P = 0.046 by Kaplan-Meier analysis) (n = 9 or 10 mice per group).
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